This resubmitted renewal application proposes a series of experiments directed at establishing unifying integrative neurologic explanations for co-morbid features of pain syndromes, balance disorders and anxiety disorders. The hypotheses explore the new perspective that there is a parallel neurochemical organization of vestibular and (interoceptive) nociceptive pathways through the parabrachial nucleus and thalamus. Specific Aim 1 tests the hypothesis that the vestibular ganglion cells have marker phenotypes that parallel findings in small to medium sized dorsal root and trigeminal ganglion cells. Specific Aim 2 uses fluorescent retrograde tract tracing, pseudorabies virus tract tracing and immunohistochemistry to test the hypothesis that the transmitter-specific organization of vestibulo-parabrachial and vestibulo-thalamic pathways parallels the organization of central pain pathways. It will test the hypothesis that there are two specific ascending vestibular pathways to the amygdala: (1) Substance P immunopositive vestibular ganglion cells AE 5OR1 immunopositive vestibular nucleus neurons AE parabrachial nucleus AE central amygdaloid nucleus. (2) P2X3 receptor positive/Isolectin B4 binding vestibular ganglion cells AE 5OR1-negative vestibular nucleus neurons AE thalamus (ventromedial, paracentral and ventroposterolateral nuclei) AE central amygdaloid nucleus. Specific Aim 3 uses fluorescent retrograde tracing methods to test the hypothesis that the caudal parabrachial nucleus projects by collaterals to the vestibular nuclei and the paratrigeminal and caudal spinal trigeminal nuclei. Specific Aim 4 tests the hypothesis that dopaminergic DRN afferents project to the medial aspect of the vestibular nuclei to a region that selectively expresses dopamine receptors. Specific Aim 5 tests the hypothesis that administration of a CGRP antagonist to a mouse model of neurogenic migraine will attenuate both plasma extravasation in the meninges and the inner ear and central c-Fos expression in trigeminal and vestibular pathways. These studies will produce fundamental new insight into parallel and convergent mechanisms for co-morbidity of migraine and balance disorders. PUBLIC HEALTH RELEVANCE: The current proposal reflects the recognition that there are very strong parallels in principles of organization of pain and balance pathways that can (1) explain the relatively prevalent co-morbidity of balance disorders (vertigo/dizziness) and migraine symptoms and (2) serve as targets for effective therapy. Five aims test explicit hypotheses regarding transmitter-specific parallel pain and vestibular pathways that converge in interoceptive components of the parabrachial nucleus and thalamus. These studies will identify potential common sites of action of opioids, dopamine antagonists and antimigraine agents (e.g., triptans) in central and peripheral components of interoceptive pain and vestibular pathways. Hence, the experiments will shed new light of mechanisms accounting for the co-morbidity of vertigo/dizziness and migraine symptoms in patients.